The present invention relates to a novel excipient for use in the manufacture of pharmaceuticals and/or nutraceuticals, and in particular, solid dosage forms such as tablets which include one or more active ingredients.
In order to prepare a solid dosage form containing one or more active ingredients (such as drugs), it is necessary that the material to be compressed into the dosage form possess certain physical characteristics which lend themselves to processing in such a manner. Among other things, the material to be compressed must be free-flowing, must be lubricated, and, importantly, must possess sufficient cohesiveness to insure that the solid dosage form remains intact after compression.
In the case of tablets, the tablet is formed by pressure being applied to the material to be tableted on a tablet press. A tablet press includes a lower punch which fits into a die from the bottom and an upper punch having a corresponding shape and dimension which enters the die cavity from the top after the tableting material fills the die cavity. The tablet is formed by pressure applied on the lower and upper punches. The ability of the material to flow freely into the die is important in order to insure that there is a uniform filling of the die and a continuous movement of the material from the source of the material, e.g. a feeder hopper. The lubricity of the material is crucial in the preparation of the solid dosage forms since the compressed material must be readily ejected from the punch faces.
Since most drugs have none or only some of these properties, methods of tablet formulation have been developed in order to impart these desirable characteristics to the material(s) which is to be compressed into a solid dosage form. Typically, the material to be compressed into a solid dosage form includes one or more excipients which impart the free-flowing, lubrication, and cohesive properties to the drug(s) which is being formulated into a dosage form.
Lubricants are typically added to avoid the material(s) being tabletted from sticking to the punches. Commonly used lubricants include magnesium stearate and calcium stearate. Such lubricants are commonly included in the final tabletted product in amounts of less than 1% by weight.
In addition to lubricants, solid dosage forms often contain diluents. Diluents are frequently added in order to increase the bulk weight of the material to be tabletted in order to make the tablet a practical size for compression. This is often necessary where the dose of the drug is relatively small.
Another commonly used class of excipients in solid dosage forms are binders. Binders are agents which impart cohesive qualities to the powdered material(s). Commonly used binders include starch, and sugars such as sucrose, glucose, dextrose, and lactose.
Disintegrants are often included in order to ensure that the ultimately prepared compressed solid dosage form has an acceptable disintegration rate in an environment of use (such as the gastrointestinal tract). Typical disintegrants include starch derivatives and salts of carboxymethylcellulose.
There are three general methods of preparation of the materials to be included in the solid dosage form prior to compression: (1) dry granulation; (2) direct compression; and (3) wet granulation.
Dry granulation procedures may be utilized where one of the constituents, either the drug or the diluent, has insufficient cohesive or flow properties to be tabletted. The method includes mixing the ingredients, slugging the ingredients, dry screening, lubricating and finally compressing the ingredients.
In direct compression, the powdered material(s) to be included in the solid dosage form is compressed directly without modifying the physical nature of the material itself.
The wet granulation procedure includes mixing the powders to be incorporated into the dosage form in, e.g., a twin shell blender or double-cone blender and thereafter adding solutions of a binding agent to the mixed powders to obtain a granulation. Thereafter, the damp mass is screened, e.g., in a 6- or 8-mesh screen and then dried, e.g., via tray drying, the use of a fluid-bed dryer, radio-frequency dryer, microwave, vacuum, or infra-red dryer.
The use of direct compression is limited to those situations where the drug or active ingredient has a requisite crystalline structure and physical characteristics required for formation of a pharmaceutically acceptable tablet. On the other hand, it is well known in the art to include one or more excipients which make the direct compression method applicable to drugs or active ingredients which do not possess the requisite physical properties. For solid dosage forms wherein the drug itself is to be administered in a relatively high dose (e.g., the drug itself comprises a substantial portion of the total tablet weight), it is necessary that the drug(s) itself have sufficient physical characteristics (e.g., cohesiveness) for the ingredients to be directly compressed.
Typically, however, excipients are added to the formulation in order to impart good flow and compression characteristics to the material as a whole which is to be compressed. Such properties are typically imparted to these excipients via a pre-processing step such as wet granulation, slugging, spray drying, spheronization, or crystallization. Useful direct compression excipients include processed forms of cellulose, sugars, and dicalcium phosphate dihydrate, among others.
A limitation of direct compression as a method of tablet manufacture is the size of the tablet. If the amount of active ingredient is high, a pharmaceutical formulator may choose to wet granulate the active with other excipients to attain an acceptably sized tablet with the desired compact strength. Usually the amount of filler/binder or excipients needed in wet granulation is less than that required for direct compression since the process of wet granulation contributes to some extent toward the desired physical properties of a tablet. Thus, despite the advantages of direct compression (such as reduced processing times and costs), wet granulation is widely used in the industry in the preparation of solid dosage forms. Many of those skilled in the art prefer wet granulation as compared to direct compression because this method has a greater probability of overcoming any problems associated with the physical characteristics of the various ingredients in the formulation, thereby providing a material which has the requisite flow and cohesive characteristics necessary to obtain an acceptable solid dosage form.
The popularity of the wet granulation process as compared to the direct compression process is based on at least three advantages. First, wet granulation provides the material to be compressed with better wetting properties, particularly in the case of hydrophobic drug substances. The addition of a hydrophilic excipient makes the surface of a hydrophobic drug more hydrophilic, easing disintegration and dissolution. Second, the content uniformity of the solid dosage forms is generally improved. Via the wet granulation method, all of the granules thereby obtained should contain approximately the same amount of drug. Thus, segregation of the different ingredients of the material to be compressed (due to different physical characteristics such as density) is avoided. Segregation is a potential problem with the direct compression method. Finally, the particle size and shape of the particles comprising the granulate to be compressed are optimized via the wet granulation process. This is due to the fact that when a dry solid is wet granulated, the binder “glues” particles together, so that they form granules which when dried exhibit enhanced flow and compression characteristics.
Due to the popularity of microcrystalline cellulose, pharmaceutical formulators have deemed it desirable to include this excipient in a formulation which is wet granulated prior to tabletting.
A processed cellulose, microcrystalline cellulose, has been utilized extensively in the pharmaceutical industry as a direct compression vehicle for solid dosage forms. Microcrystalline cellulose is commercially available under the tradename Emcocel® from JRS Pharma and as Avicel® from FMC Corp. Compared to other directly compressible excipients, microcrystalline cellulose is generally considered to exhibit superior compressibility and disintegration properties.
Silicified microcrystalline cellulose is commercially available as Prosolv® SMCC and is a high functionality excipient that imparts superior flow, compaction and dispersion to a formulation. When used in direct compression, Prosolv® SMCC can replace granulations and provide uniform tablets, while significantly reducing excipient numbers and levels. Prosolv® SMCC may enable direct compression while avoiding wet granulation, and may provide increased production capacity and improved compactability. On the other hand, Prosolv® SMCC provides excellent compressibility even when wet granulated, and so is useful in wet granulated formulations, as well.
Neusilin® is a totally synthetic magnesium aluminometasilicate (MAS) with exceptional excipient properties to improve API delivery and the quality of oral solid dosage forms, commercially available from Fuji Chemical Industry Co., Ltd. Neusilin is a multifunctional excipient that can be used in both direct compression and wet granulation of solid dosage forms. Neusilin is widely used for improvement of the quality of tablets, powder, granules and capsules. In its product description, it is stated that the most suitable grade for converting oil to powder is Neusilin® US2. When the oil load is comparatively high, an addition of 0.5 to 2% UFL2 is said to improve flowability substantially. Neusilin® UFL2 alone at 0.5% can resolve sticking issues of oily formulations. Neusilin® is said to potentially resolve problems associated with tabletting and improve efficiency of poorly water soluble drugs in a solid dispersion, as well as improve dissolution and bioavailability. Neusilin® is also said to be useful in developing a Self Emulsifying Drug Delivery System (SEDDS) or a Self Nano-Emulsifying Drug Delivery System (SNEDDS), by aiding in the conversion of the liquid SEDDS/SNEDDS into a solid one. Neusilin® is further described as being safe with no reports of adverse reactions and is an accepted ingredient by the U.S. Pharmacopoeia/National Formulary and Japanese Pharmaceutical Codex. Based on the usage as an excipient in various formulations in Japan, Neusilin® up to 1.05 g can be used for oral uptake per day. (Encyclopedia of Pharmaceutical Additives, Japan, 2005). Neusilin® (Alkaline grades) is also approved as antacid active ingredient where the maximum dosage is 4 g/day. (Japanese approved list of manufacturing and import of gastrointestinal drugs). There are no established maximum oral intake limits specified by US-FDA. Neusilin® is described in U.S. Patent Publication No. 2010/0196475, hereby incorporated by reference in its entirety.
Oily drugs, or drugs which are dissolvable in oil, are typically prepared as soft gel capsules. Although there are many commonly used excipients that will absorb oils or oily drugs, these excipients can only absorb a limited amount of oil when the goal is to manufacture tablets, and many do not retain the oil sufficiently to prevent its partial loss during the compression process.